Aging modulated by the Drosophila insulin receptor through distinct structure-defined mechanisms

Abstract Mutations of the Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions...

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Bibliographic Details
Published in:Genetics (Austin) 2021-02, Vol.217 (2)
Main Authors: Yamamoto, Rochele, Palmer, Michael, Koski, Helen, Curtis-Joseph, Noelle, Tatar, Marc
Format: Article
Language:English
Subjects:
Adapter proteins
Adaptor proteins
Aging
AKT protein
Domains
Drosophila
Egg production
Fecundity
Fruit flies
Genetics
Genotypes
Heterozygotes
Homologous recombination
Homology
Insects
Insulin
Insulin-like growth factors
Investigation
Kinases
Life history
Life span
Mutation
Phosphorylation
Pleiotropy
Protein-tyrosine kinase receptors
Receptors
Reproduction
Signalling systems
Structure-function relationships
Tyrosine
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Summary:Abstract Mutations of the Drosophila melanogaster insulin/IGF signaling system slow aging, while also affecting growth and reproduction. To understand this pleiotropy, we produced an allelic series of single codon substitutions in the Drosophila insulin receptor, InR. We generated InR substitutions using homologous recombination and related each to emerging models of receptor tyrosine kinase structure and function. Three mutations when combined as trans-heterozygotes extended lifespan while retarding growth and fecundity. These genotypes reduced insulin-stimulated Akt phosphorylation, suggesting they impede kinase catalytic domain function. Among these genotypes, longevity was negatively correlated with egg production, consistent with life-history trade-off theory. In contrast, one mutation (InR353) was located in the kinase insert domain, a poorly characterized element found in all receptor tyrosine kinases. Remarkably, wild-type heterozygotes with InR353 robustly extended lifespan without affecting growth or reproduction and retained capacity to fully phosphorylate Akt. The Drosophila insulin receptor kinase insert domain contains a previously unrecognized SH2 binding motif. We propose the kinase insert domain interacts with SH2-associated adapter proteins to affect aging through mechanisms that retain insulin sensitivity and are independent of reproduction.
ISSN:1943-2631
0016-6731
1943-2631
DOI:10.1093/genetics/iyaa037